A Self-Assembling LYTAC Mediates CTGF Degradation and Remodels Inflammatory Tumor Microenvironment for Triple-Negative Breast Cancer Therapy.

As a multifunctional extracellular protein, connective tissue growth factor (CTGF/CCN2) is significantly associated with the progression and prognosis of triple-negative breast cancer (TNBC). However, current blockade therapies targeting CTGF's multiple domains are limited, creating substantial challenges in treatment. Lysosome-targeting chimeras (LYTACs) have emerged as a promising approach for achieving complete protein degradation and inhibiting CTGF's various bioactivities. In this study, a self-assembling LYTAC nanoplatform, NanoCLY, designed to tumor microenvironment (TME)-responsively degrade CTGF is presented. The complete degradation of CTGF downregulates the TGF-β signaling pathway and disrupts the CTGF-IL-6 cell crosstalk within the TME, which further inhibits the activation of inflammatory cancer-associated fibroblasts (CAFs) and alleviates the inflammatory TME. Notably, the anti-TNBC effect of LYTAC-based CTGF degradation therapy surpasses that of antibody-based blockade therapy in both in vitro and in vivo models. The findings provide a proof of concept for CTGF degradation in TNBC and introduce the first CTGF-LYTAC nanoplatform aimed at TME-directed therapy.